Cell signaling via 3′-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity. The enzyme responsible for generating these phosphorylated signaling products, phosphatidylinositol 3-kinase (PI 3-kinase; PI3K), was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at the 3′-hydroxyl of the inositol ring.
PI 3-kinase activation, is believed to be involved in a range of cellular responses including cell growth, differentiation, and apoptosis. FIG. 1 shows some cellular pathways by which PI3K (represented by p110 and p85) participates in solid tumor activation.
The initial purification and molecular cloning of PI3-kinase revealed that it was a heterodimer consisting of p85 and p110 subunits. Four distinct Class I PI3Ks have been identified, designated PI3K α, β, δ, and γ, each consisting of a distinct p110 catalytic subunit and a regulatory subunit. More specifically, three of the catalytic subunits, i.e., p110α, p110β and p110δ, each interact with the same regulatory subunit, p85; whereas p110γ interacts with a distinct regulatory subunit, p101. The patterns of expression of each of these PI3Ks in human cells and tissues are also distinct.
Identification of the p110δ isoform of PI 3-kinase is described in Chantry et al., J. Biol. Chem., 272:19236-41 (1997). It was observed that the human p110δ isoform is expressed in a tissue-restricted fashion. It is expressed at high levels in lymphocytes and lymphoid tissues, suggesting that the protein might play a role in PI3-kinase-mediated signaling in the immune system. The p110β isoform of PI3K may also play a role in PI3K-mediated signaling in certain cancers. FIG. 2 illustrates the relative amounts of these isoforms of p110 in a number of different cancer cell lines. Some solid tumors exhibit little or no p110α, and many have low levels of p110δ, but all of the ones tested showed significant levels of p110β.
There is a need for a treatment of PI3K-mediated disorders relating to cancers, inflammatory diseases, and autoimmune diseases. Quinazolinone compounds have been described as generally useful for treating mainly hematologic cancers that express relatively high levels of p110δ, because the quinazolinones are more active as inhibitors of p110δ. Other PI3K inhibitors are under development for treatment of solid tumors, but they appear to be non-selective inhibitors of several isoforms of p110, or inhibitors mainly of p110α. For example, XL-147 inhibits p110α and p110δ and p110γ with similar IC-50's according to Exelixis, and has 10× lower activity on p110β; BEZ235 is described as a pan-PI3K inhibitor that also acts on mTOR; and GDC-0941 is described as a p110α inhibitor. Inhibitors with lower selectivity, or with higher levels of p110α activity, could be expected to have off-target activities; p110α, for example, is involved in regulation of glucose and insulin levels. The present invention provides a specific isomer of one quinazolinone compound that is particularly useful for the treatment of solid tumors. While it is more active on p110δ than other isoforms of PI3K, this compound's ability to treat solid tumors is believed to be due to its relatively high activity as an inhibitor of p110β combined with a high level of oral bioavailability, and it exhibits relatively low levels of functional activity against p110α.